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Definitions

• This invention relates generally to novel hydantoin derivatives that can inhibit matrix metalloproteinases (MMPs), a disintegrin and metalloproteases (ADAMs) and/or tumor necrosis factor alpha - converting enzyme (TACE) and in so doing prevent the release of tumor necrosis factor alpha (TNF- ⁇ ), pharmaceutical compositions comprising such compounds, and methods of treatment using such compounds.
• MMPs matrix metalloproteinases
• ADAMs disintegrin and metalloproteases
• TACE tumor necrosis factor alpha - converting enzyme
• Osteo- and rheumatoid arthritis are destructive diseases of articular cartilage characterized by localized erosion of the cartilage surface. Findings have shown that articular cartilage from the femoral heads of patients with OA, for example, had a reduced incorporation of radiolabeled sulfate over controls, suggesting that there must be an enhanced rate of cartilage degradation in OA (Mankin et al. J. Bone Joint Surg. 52A (1970) 424-434).
• MPs Metalloproteases
• MMPs are a family of over 20 different enzymes that are involved in a variety of biological processes important in the uncontrolled breakdown of connective tissue, including proteoglycan and collagen, leading to resorption of the extracellular matrix. This is a feature of many pathological conditions, such as RA and OA, corneal, epidermal or gastric ulceration; tumor metastasis or invasion; periodontal disease and bone disease. Normally these catabolic enzymes are tightly regulated at the level of their synthesis as well as at their level of extracellular activity through the action of specific inhibitors, such as alpha-2-macroglobulins and TIMPs (tissue inhibitor of MPs), which form inactive complexes with the MMP's.
• specific inhibitors such as alpha-2-macroglobulins and TIMPs (tissue inhibitor of MPs)
• Tumor necrosis factor alpha is a cell-associated cytokine that is processed from a 26 kDa precursor form to a 17 kd active form. See Black R.A. "Tumor necrosis factor-alpha converting enzyme” lnt J Biochem Cell Biol. 2002 Jan; 34(1 ):1-5 and Moss ML, White JM, Lambert MH, Andrews RC 1 TACE and other ADAM proteases as targets for drug discovery" Drug Discov Today. 2001 Apr 1 ;6(8):417-426, each of which is incorporated by reference herein.
• TNF- ⁇ has been shown to play a pivotal role in immune and inflammatory responses. Inappropriate or over-expression of TNF- ⁇ is a hallmark of a number of diseases, including RA, Crohn's disease, multiple sclerosis, psoriasis and sepsis. Inhibition of TNF- ⁇ production has been shown to be beneficial in many preclinical models of inflammatory disease, making inhibition of TNF- ⁇ production or signaling an appealing target for the development of novel anti-inflammatory drugs.
• TNF- ⁇ is a primary mediator in humans and animals of inflammation, fever and acute phase responses, similar to those observed during acute infection and shock. Excess TNF- ⁇ has been shown to be lethal. Blocking the effects of TNF- ⁇ with specific antibodies can be beneficial in a variety of conditions, including autoimmune diseases such as RA (Feldman et al, Lancet, (1994) 344, 1105), non-insulin dependent diabetes mellitus (Lohmander L. S. et al., Arthritis Rheum. 36 (1993) 1214-22) and Crohn's disease (Macdonald T. et al., Clin. Exp. Immunol. 81 (1990) 301).
• RA Paindman et al, Lancet, (1994) 344, 1105
• non-insulin dependent diabetes mellitus Lihmander L. S. et al., Arthritis Rheum. 36 (1993) 1214-22
• Crohn's disease Macdonald T. e
• TNF- ⁇ Compounds that inhibit the production of TNF- ⁇ are therefore of therapeutic importance for the treatment of inflammatory disorders. Recently it has been shown that metalloproteases, such as TACE, are capable of converting TNF- ⁇ from its inactive to active form (Gearing et al Nature, 1994, 370, 555). Since excessive TNF- ⁇ production has been noted in several disease conditions also characterized by MMP-mediated tissue degradation, compounds which inhibit both MMPs and TNF- ⁇ production may also have a particular advantage in diseases where both mechanisms are involved.
• TACE is a member of the ADAM family of type I membrane proteins and mediates the ectodomain shedding of various membrane-anchored signaling and adhesion proteins. TACE has become increasingly important in the study of several diseases, including inflammatory disease, because of its role in cleaving TNF- ⁇ from its "stalk" sequence and thus releasing the soluble form of the TNF- ⁇ protein (Black R.A. lnt J Biochem Cell Biol. 200234,1-5).
• PCT Publications WO2004024698 and WO2004024715 disclose sulphonamide derivatives that are potential inhibitors of MMPs.
• PCT Publications WO2004056766, WO2003053940 and WO2003053941 also describe potential inhibitors of TACE and MMPs.
• PCT Publication WO2006/019768 refers to hydantoin derivatives that are TACE inhibitors.
• the present invention provides a novel class of compounds as inhibitors of TACE, the production of TNF- ⁇ , MMPs, ADAMs, aggrecanase, or any combination thereof, methods of preparing such compounds, pharmaceutical compositions comprising one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition or amelioration of one or more diseases associated with TACE, aggrecanaseTNF- ⁇ , MMPs, ADAMs or any combination thereof using such compounds or pharmaceutical compositions.
• the present application discloses a compound represented by Formula (I):
• ring A is selected from the group consisting of aryl and heteroaryl, each of which is substituted with -Y-R 1 and -Z-R 2 as shown;
• X is selected from the group consisting of -S-.-O-, -S(O) 2 -, S(O)-,
• T is alkynyl
• V is selected from the group consisting H, alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, and N-oxides of said heteroaryl and heterocyclyl, wherein when each of said cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, and N oxides of said heteroaryl and heterocyclyl contains two radicals on same or adjacent carbon atoms, said radicals may optionally be taken together with the carbon atom(s) to which they are attached to form a five- to eight-membered cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl ring, wherein each of the aforementioned cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl, optionally with said five- to eight-membered cycloalkyl, cycloalkenyl, aryl, heterocycl
• Y is selected from the group consisting of a covalent bond, -(C(R 4 J 2 )D-, -N(R 4 )-, -C(O)N(R 4 )-, -N(R 4 )C(O)-, -N(R 4 JC(O)N(R 4 )-, -S(O) 2 N(R 4 )-, -N(R 4 )-S(O) 2 -, -O-.-S-, -C(O)-, -S(O)-, and -S(O) 2 -;
• Z is selected from the group consisting of a covalent bond, -(C(R 4 ) 2 ) n -,
• R is selected from the group consisting of H, cyano, alkynyl, halogen, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, and heterocyclyl, wherein when each of said cycloalkyl, heterocyclyl, aryl and heteroaryl contains two radicals on adjacent carbon atoms, said radicals may optionally be taken together with the carbon atoms to which they are attached to form a five- to eight- membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring; wherein each of the R 1 alkyl, alkynyl, aryl, heteroaryl, and heterocyclyl, optionally with the five or six-membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring is ⁇ nsubstituted or optionally independently substituted with one to four R 20 moieties which can be the same or different; with the proviso that when Y is -
• R is selected from the group consisting of H, cyano, alkynyl, halogen, alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, and heterocyclyl, wherein when each of said cycloalkyl, heterocyclyl, aryl and heteroaryl contains two radicals on adjacent carbon atoms, said radicals may optionally be taken together with the carbon atoms to which they are attached to form a five- to eight- membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring; wherein each of the R 2 alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, optionally with the five or six-membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring is unsubstituted or optionally independently substituted with one to four R 20 moieties which can be the same or different; with the proviso that when Y is - N
• each R is the same or different and is independently selected from the group consisting of H, alkyl, cycloalkyl, haloalkyl, hydroxy, -alkylcycloalkyl, - alkyl-N(alkyl)2, heterocyclyl, aryl, and heteroaryl;
• R is selected from the group consisting of cyano, nitro,
• the ring labeled A is selected from the group consisting of aryl and heteroaryl, each of which is substituted with -Y-R 1 and -Z-R 2 as shown;
• X is selected from the group consisting of -S-,-O-, -C(R ) 2 - or -N(R )- ;
• T is absent or present, and if present, T is selected from the group consisting of H (with U and V being absent), alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl-, and arylalkyl-, said aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl-, and arylalkyl- being optionally fused with one or more moieties selected from the group consisting of aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl, wherein each of any of the aforementioned alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl groups of T is unsubstituted or optionally independently substituted with one to four R 10 moieties which can be the same or different, each R 10 moiety being
• U is absent or present, and if present U is selected from the group consisting of alkynyl, -C(O)-, -C(O)O-, and -C(O)NR 4 -;
• V is absent or present, and if present V is selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl-, cycloalkyl, alkylaryl-, and arylalkyl-, said aryl, heteroaryl, heterocyclyl, heterocyclylalkyl-, cycloalkyl, alkylaryl- and arylalkyl- being optionally fused with one or more moieties selected from the group consisting of aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl, wherein each of any of the aforementioned alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl is unsubstituted or optionally independently substituted with one to four R 10 moieties which can be the same or different, each R 10 moiety being independently selected from the group of R 10 moieties below;
• Y is selected from the group consisting of a covalent bond, -(C(R 4 ) 2 ) n -,
• Z is selected from the group consisting of a covalent bond, -(C(R 4 ) 2 ) n -,
• R is selected from the group consisting of H, -OR 4 , cyano, -C(O)OR 4 , -C(O)N(R 4 ) 2 , halogen, alkyl, fluoroalkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and arylalkyl, wherein each of the alkyl, fluoroalkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and arylalkyl groups of R is unsubstituted or optionally independently substituted with one to four R 20 moieties which can be the same or different, each R 20 moiety being independently selected from the group of R 20 moieties below, with the proviso that when Y is present and Y is N, S or O, then R 1 is not halogen or cyano;
• R is selected from the group consisting of H, -OR 4 , cyano, -C(O)OR 4 , -C(O)N(R 4 )2, halogen, alkyl, fluoroalkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and arylalkyl, wherein each of the alkyl, fluoroalkyl, aryl,
• R 2 heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and arylalkyl groups of R is unsubstituted or optionally independently substituted with one to four R 20 moieties which can be the same or different, each R 20 moiety being independently selected from the group of R 20 moieties below, with the proviso that when Z is present and Z is N, S or O, then R 2 is not halogen; each R 3 is the same of different and is independently selected from the group consisting of H, alkyl, and aryl;
• each R is the same or different and is independently selected from the group consisting of H, alkyl, heterocyclyl, aryl, and heteroaryl;
• R is selected from the group consisting of cyano, — OR , -SR , -N(R ) 2 , -S(O)R 4 -, -S(O) 2 R 4 -, -N(R 4 JS(O) 2 R 4 , -S(O) 2 N(R 4 J 2 , -O(fluoroalkyl), -C(O)OR 4 , -C(O)N(R 4 )2, halogen, alkyl, fluoroalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl, wherein each of the alkyl, fluoroalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl groups of R is unsubstituted or optionally independently substituted with one to four R 30 moieties which can be the same or different, each R 30 moiety being
• R is selected from the group consisting of halogen, alkyl, fluoroalkyl,
• R R i iss sseelleecctteedd ffrroonm the group consisting of halogen, alkyl, fluoroalkyl, -N(R 4 J 2 , and -C(O)N(R 4 J 2 .
• the compounds of Formula I can be useful as inhibitors of TACE and may be useful in the treatment and prevention of diseases associated with TACE, TNF- ⁇ , MMPs 1 ADAMs or any combination thereof.
• the present invention provides a novel class of inhibitors of TACE, aggrecanase, the production of TNF- ⁇ , MMPs 1 ADAMs or any combination thereof, pharmaceutical compositions containing one or more of the compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention or amelioration of one or more of the symptoms of inflammation.
• the present invention provides compounds which are represented by structural Formula (I)-(IV) above or a pharmaceutically acceptable salt, solvate, ester or isomer thereof, wherein the various moieties are as described above.
• the isomer referred to the in the preceding paragraph is a stereoisomer.
• the labeled ring A is selected from the group consisting of phenyl, thiophenyl, pyridyl, pyrimidyl, and
• ring A is phenyl which is substituted with -Y-R 1 and -Z-R 2 as shown.
• X is selected from the group consisting of -(C(R 3 ) 2 ) m - and -N(R 3 )-.
• X is X is -(C(R 3 )2)m. wherein m is 1 or 2.
• 1 X is is ⁇ iC(R 3 ) 2 ) m , wherein m is
• R 3 is H.
• X is is -(C(R 3 ) 2 )m, wherein m 1 , and wherein R 3 is H.
• T is -CsC-.
• V is selected from the group consisting of H, aryl, heteroaryl, and N-oxide of said heteroaryl; wherein when each of the aforementioned aryl, and heteroaryl contains two radicals on same or adjacent carbon atoms, said radicals may optionally be taken together with the carbon atom(s) to which they are attached to form a five or six-membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring; wherein said aryl and heteroaryl optionally with said five or six-membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring is unsubstituted or optionally substituted with one to four R 10 moieties which can be the same or different.
• V is selected from the group consisting of phenyl, naphthyl, pyrrolyl, furanyl, thiophenyl, pyrrazolyl, benzopyrazolyl, imidazoly, benzimidazolyl, furazanyl, pyridyl, pyridyl-N-oxide, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isopquinolinyl, quinazolinyl, pteridinyl, tetrazolyl, oxazolyl, isothiazolyl, thiazolyl,
• each R is the same or different and is independently selected from the group consisting of H, alkyl, cycloalkyl, haloalkyl, hydroxy, -alkylcycloalkyl, -alkyl-N(alkyl) 2 , heterocyclyl, aryl, and heteroaryl; and
• R 10 is selected from the group consisting of nitro, alkyl, halogen, haloalkyl, haloalkoxy, alkoxy, cyano, -S(O) 2 - alkyl, -NH 2 , -NH(alkyl), -N(alkyl) 2 , cycloalkyl, aryl, heteroaryl, heterocyclyl, - alkyl-heterocyclyl, -cycloalkyl-NH 2 , -S(O) 2 -NH 2 , -S(O) 2 alkyl, -C(O)NH 2 , hydroxy, -C(O)N(H)(cycloalkyl), -C(O)N(H)(alkyl), -N(H)(cycloalkyl), -C(O)O- alkyl, -C(O)OH, -S(O) 2 N(H)(alkyl), -C(O) 2 N(H
• R 10 is selected from the group consisting of hydrogen, nitro, methyl, fluoro, bromo, trifluoromethyl, chloro, difluoromethoxy, trifluoromethoxy, methoxy, hydroxy!, cyano, -S(O) 2 CHs, - NH 2 , isopropyl, cyclopropyl, -cyclopropyl-NH 2 ,
• Y is selected from the group consisting of a covalent bond and -O-.
• Y is a covalent bond. In another embodiment, in Formula (I), Y is -O-.
• Z is selected from the group consisting of a covalent bond and -O-.
• Z is -O-.
• R 1 is selected from the group consisting of hydrogen, cyano, halogen, alkyl, aryl, heteroaryl, haloalkyl, and alkynyl; wherein said R 1 alkyl is unsubstituted or substituted with an aryl, heteroaryl, or heterocyclyl, wherein when said aryl, heteroaryl, or heterocyclyl contains two radicals on adjacent carbon atoms, said radicals may optionally be taken together with the carbon atoms to which they are attached to form a five- to eight-membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring; wherein said aryl, heteroaryl or heterocyclyl substitutent of said R 1 alkyl optionally with said five- to eight-membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring is unsubstituted or optionally independently substituted with one to four R 20 moieties.
• R 2 is selected from the group consisting of hydrogen, cyano, halogen, alkyl, aryl, heteroaryl, haloalkyl, and alkynyl; wherein said R 1 alkyl is unsubstituted or substituted with an aryl, heteroaryl, or heterocyclyl, wherein when said aryl, heteroaryl, or heterocyclyl contains two radicals on adjacent carbon atoms, said radicals may optionally be taken together with the carbon atoms to which they are attached to form a five- to eight-membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring; wherein said aryl, heteroaryl or heterocyclyl substitutent of said R 1 alkyl optionally with said five- to eight-membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring is unsubstituted or optionally independently substituted with one to four R 20 moieties.
• R 1 is halogen or cyano.
• R 1 is fluoro, chloro, or cyano.
• Y is -O-, and R 1 is selected from the group consisting of alkyl, haloalkyl, and alkynyl; wherein said R 1 alkyl is unsubstituted or substituted with a heteroaryl, wherein when said heteroaryl contains two radicals on adjacent carbon atoms, said radicals may optionally be taken together with the carbon atoms to which they are attached to form a five- or six-membered aryl; wherein said heteroaryl substituent of said R 1 alkyl, optionally with said five- or six-membered aryl is substituted with alkyl.
• R 1 is selected from the group consisting of CH 3 , -CH 2 -C ⁇ C-CH 3 , difluoromethyl, and
• the compound of Formula (I) is represented by the compound of formula (III):
• X is -CH 2 -.
• the compound of Formula (I) is represented by the compound of formula (IV):
• X is -CH2-.
• the compound of Formula (I) is selected from the group consisting of compounds listed in the table below, or a pharmaceutically acceptable salt, solvate, ester or isomer thereof. This table also lists the mass spectroscopy data and the Ki rating for each compound.
• the compounds of Formula (I) are selected from the group consisting of;
• the compounds of Formula (I) are selected from the group consisting of: or a phar
• Patient includes both human and animals.
• “Mammal” means humans and other mammalian animals.
• Alkyl means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl” means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched.
• the alkyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH(alkyl), -NH(cycloalkyl), -N(alkyl)2, carboxy and -C(O)O-alkyl.
• substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH(alkyl), -NH(cycloalkyl), -N(alkyl)2, carboxy and -C(O)O-alkyl.
• suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-
• Alkenyl means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain.
• Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain.
• Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain.
• “Lower alkenyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched.
• suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2- enyl, n-pentenyl, octenyl and decenyl.
• Alkynyl means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain.
• Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain.
• Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain.
• “Lower alkynyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched.
• Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3- methylbutynyl.
• substituted alkynyl means that the alkynyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl.
• Aryl means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms.
• the aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein.
• suitable aryl groups include phenyl and naphthyl.
• Heteroaryl means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination.
• heteroaryls contain about 5 to about 6 ring atoms.
• the "heteroaryl” can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein.
• the prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom.
• a nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide.
• Heteroaryl may also include a heteroaryl as defined above fused to an aryl as defined above.
• Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N- substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1 ,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1 ,2-a]pyridinyl, imidazo[2,1- bjthiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl
• Aralkyl or “arylalkyl” means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2- phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.
• Alkylaryl means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non- limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl.
• Cycloalkyl means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above.
• Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
• Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbomyl, adamantyl and the like.
• Cycloalkenyl means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms.
• the cycloalkenyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above.
• suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohepta-1 ,3-dienyl, and the like.
• Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl.
• Halogen means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine.
• Ring system substituent means a substituent attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system.
• Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio
• Ring system substituent may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system.
• Examples of such moiety are methylene dioxy, ethylenedioxy, -C(CHs) 2 - and the like which form moieties such as, for example:
• Heterocyclyl means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
• Preferred heterocyclyls contain about 5 to about 6 ring atoms.
• the prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
• Any -NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), -N(CBz), -N(Tos) group and the like; such protections are also considered part of this invention.
• the heterocyclyl can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein.
• the nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
• heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like.
• Heterocyclyl may also mean a single moiety (e.g., carbonyl) which simultaneously replaces two available hydrogens on the same carbon atom on a ring system. Example of such moiety is pyrrolidone:
• Alkynylalkyl means an alkynyl-alkyl- group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety is through the alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl.
• Heteroaralkyl means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl.
• Hydroxyalkyl means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.
• acyl means an H-C(O)-, alkyl-C(O)- or cycloalkyl-C(O)-, group in which the various groups are as previously described.
• the bond to the parent moiety is through the carbonyl.
• Preferred acyls contain a lower alkyl.
• suitable acyl groups include formyl, acetyl and propanoyl.
• Aroyl means an aryl-C(O)- group in which the aryl group is as previously described.
• the bond to the parent moiety is through the carbonyl.
• suitable groups include benzoyl and 1- naphthoyl.
• Alkoxy means an alkyl-O- group in which the alkyl group is as previously described.
• suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
• the bond to the parent moiety is through the ether oxygen.
• Aryloxy means an aryl-O- group in which the aryl group is as previously described.
• suitable aryloxy groups include phenoxy and naphthoxy.
• the bond to the parent moiety is through the ether oxygen.
• Alkyloxy means an aralkyl-O- group in which the aralkyl group is as previously described.
• suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.
• the bond to the parent moiety is through the ether oxygen.
• Alkylthio means an alkyl-S- group in which the alkyl group is as previously described.
• suitable alkylthio groups include methylthio and ethylthio.
• the bond to the parent moiety is through the sulfur.
• Arylthio means an aryl-S- group in which the aryl group is as previously described.
• suitable arylthio groups include phenylthio and naphthylthio.
• the bond to the parent moiety is through the sulfur.
• Alkylthio means an aralkyl-S- group in which the aralkyl group is as previously described.
• Non-limiting example of a suitable aralkylthio group is benzylthio.
• the bond to the parent moiety is through the sulfur.
• Alkoxycarbonyl means an alkyl-O-CO- group.
• suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl.
• the bond to the parent moiety is through the carbonyl.
• Aryloxycarbonyl means an aryl-O-C(O)- group.
• suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.
• the bond to the parent moiety is through the carbonyl.
• Aralkoxycarbonyl means an aralkyl-O-C(O)- group.
• Non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is through the carbonyl.
• Alkylsulfonyl means an alkyl-S(O2)- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.
• Arylsulfonyl means an aryl-S(O2>- group. The bond to the parent moiety is through the sulfonyl.
• substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
• stable compound 1 or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
• isolated or “in isolated form” for a compound refers to the physical state of said compound after being isolated from a synthetic process or natural source or combination thereof.
• purified or “in purified form” for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan, in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
• any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and Tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.
• a functional group in a compound is termed "protected”
• Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene etal, Protective Groups in organic Synthesis (1991), Wiley, New York.
• variable e.g., aryl, heterocycle, R 2 , etc.
• its definition on each occurrence is independent of its definition at every other occurrence.
• composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
• Prodrugs and solvates of the compounds of the invention are also contemplated herein.
• the term "prodrug”, as employed herein, denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of Formula I or a salt and/or solvate thereof.
• a discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, both of which are incorporated herein by reference thereto.
• the term “prodrug” means a compound (e.g.
• a drug precursor that is transformed in vivo to yield a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound.
• the transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood.
• a discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
• a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (Ci-C 8 )alkyl, (C 2 -Ci 2 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N- (alkoxycarbon
• a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (Cr C 6 )alkanoyloxymethyl, 1 -((C-i-CeJalkanoyloxyJethyl, 1 -methyl-1-((C-r C 6 )alkanoyloxy)ethyl, (Ci-Cejalkoxycarbonyloxymethyl, N-(Ci- C 6 )alkoxycarbonylaminomethyl, succinoyl, (Ci-C ⁇ jalkanoyl, ⁇ -amino(Ci- C4)alkanyl, arylacyl and ⁇ -aminoacyl, or ⁇ -aminoacyl- ⁇ -aminoacyl, where each ⁇ -aminoacyl group is independently selected from the naturally occurring L- amino acids, P(O)(OH) 2 , -P(
• a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'- carbonyl where R and R' are each independently (Ci-C 10 )alkyl, (C 3 -C 7 ) cycloalkyl, benzyl, or R-carbonyl is a natural ⁇ -aminoacyl or natural ⁇ - aminoacyl, -C(OH)C(O)OY 1 wherein Y 1 is H, (Ci-C 6 )alkyl or benzyl, — C(OY 2 )Y 3 wherein Y 2 is (CrC 4 ) alkyl and Y 3 is (Ci-C 6 )alkyl, carboxy (Ci- C ⁇ jalkyl, amino(CrC4)alkyl or mono-N — or di-N,N-(C
• R-carbonyl RO-carbonyl
• Solvate means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
• Solvate encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.
• “Hydrate” is a solvate wherein the solvent molecule is H2O.
• Effective amount or “therapeutically effective amount” is meant to describe an amount of compound or a composition of the present invention effective in inhibiting TACE, the production of TNF- ⁇ , MMPs, ADAMS or any combination thereof and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.
• the compounds of Formula I can form salts which are also within the scope of this invention.
• Reference to a compound of Formula I herein is understood to include reference to salts thereof, unless otherwise indicated.
• the term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
• zwitterions inner salts may be formed and are included within the term "salt(s)" as used herein.
• Salts of the compounds of the Formula I may be formed, for example, by reacting a compound of Formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
• Exemplary acid addition salts include acetates, ascorbates, benzoates, benze ⁇ esulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydro bromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like.
• Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
• Basic nitrogen-containing groups may be quartemized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g.
• All stereoisomers for example, geometric isomers, optical isomers and the like
• of the present compounds including those of the salts, solvates and prodrugs of the compounds as well as the salts and solvates of the prodrugs
• those which may exist due to asymmetric carbons on various substituents including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl).
• Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
• the chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
• the use of the terms "salt”, “solvate” "prodrug” and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
• the compounds according to the invention have pharmacological properties; in particular, the compounds of Formula I can be inhibitors of TACE, aggrecanase, TNF- ⁇ and/or MMP activity.
• the invention provides a pharmaceutical composition comprising as an active ingredient at least one compound of formula (I).
• the invention provides a pharmaceutical composition of formula (I) additionally comprising at least one pharmaceutically acceptable carrier.
• the invention provides a method of treating disorders associated with TACE, aggrecanase, TNF- ⁇ , MMPs, ADAMs or any combination thereof, said method comprising administering to a patient in need of such treatment an effective amount of at least one compound of formula (I).
• the invention provides a use of a compound of formula (I) for the manufacture of a medicament to treat disorders associated with TACE 1 aggrecanase, TNF- ⁇ , MMPs, ADAMs or any combination thereof.
• the compounds of Formula (I) can have anti-inflammatory activity and/or immunomodulatory activity and can be useful in the treatment of diseases including but not limited to septic shock, haemodynamic shock, sepsis syndrome, post ischaemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancers such as cutaneous T-cell lymphoma, diseases involving angiogenesis, autoimmune diseases, skin inflammatory diseases, inflammatory bowel diseases such as Crohn's disease and colitis, OA and RA, ankylosing spondylitis, psoriatic arthritis, adult Still's disease, ureitis, Wegener's granulomatosis, Behcehe disease, Sjogren's syndrome, sarcoidosis, polymyositis, dermatomyositis, multiple sclerosis, sciatica, complex regional pain syndrome, radiation damage, hyperoxic alveolar injury, period
• the invention provides a method of preparing a pharmaceutical composition for treating the disorders associated with TACE, aggrecanase, TNF- ⁇ , MMPs, ADAMs or any combination thereof, said method comprising bringing into intimate contact at least one compound of formula (I) and at least one pharmaceutically acceptable carrier.
• the invention provides a compound of formula (I) exhibiting TACE, TNF- ⁇ , MMPs, ADAMs or any combination thereof inhibitory activity, including enantiomers, stereoisomers and tautomers of said compound, and pharmaceutically acceptable salts, solvates, or esters of said compound, said compound being selected from the compounds of structures listed in Table 1001 set forth above.
• the invention provides a pharmaceutical composition for treating disorders associated with TACE, aggrecanase, TNF- ⁇ , MMP, ADAM or any combination thereof in a subject comprising, administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, or isomer thereof.
• the invention provides a compound of formula (I) in purified form.
• the invention provides a method of treating a condition or disease mediated by TACE, MMPs, TNF- ⁇ , aggrecanase, or any combination thereof in a subject comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester or isomer thereof.
• the invention provides a method of treating a condition or disease selected from the group consisting of rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, solid tumor growth and tumor invasion by secondary metastases, neovascular glaucoma, inflammatory bowel disease, multiple sclerosis and psoriasis in a subject, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester or isomer thereof.
• a condition or disease selected from the group consisting of rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, solid tumor growth and tumor invasion by secondary metastases, neovascular glaucoma, inflammatory bowel disease, multiple sclerosis and psoriasis in a subject, comprising: administering to the subject in need of such treatment a therapeutically effective amount
• the invention provides a method of treating a condition or disease selected from the group consisting of fever, cardiovascular conditions, hemorrhage, coagulation, cachexia, anorexia, alcoholism, acute phase response, acute infection, shock, graft versus host reaction, autoimmune disease and HIV infection in a subject comprising administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, or isomer thereof.
• the invention provides a method of treating a condition or disease selected from the group consisting of septic shock, haemodynamic shock, sepsis syndrome, post ischaemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancers such as cutaneous T-cell lymphoma, diseases involving angiogenesis, autoimmune diseases, skin inflammatory diseases, inflammatory bowel diseases such as Crohn's disease and colitis, osteo and rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, adult Still's disease, ureitis, Wegener's granulomatosis, Behcehe disease, Sjogren's syndrome, sarcoidosis, polymyositis, dermatomyositis, multiple sclerosis, sciatica, complex regional pain syndrome, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV
• the invention provides a method of treating a condition or disease associated with COPD, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of Formula (I) or a pharmaceutically acceptable salt, solvate, ester or isomer thereof.
• the invention provides a method of treating a condition or disease associated with rheumatoid arthritis, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, or isomer thereof.
• the invention provides a method of treating a condition or disease associated with Crohn's disease, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester or isomer thereof.
• the invention provides a method of treating a condition or disease associated with psoriasis, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, or isomer thereof.
• the invention provides a method of treating a condition or disease associated with ankylosing spondylitis, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester or isomer thereof.
• the invention provides a method of treating a condition or disease associated with sciatica, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester or isomer thereof.
• the invention provides a method of treating a condition or disease associated with complex regional pain syndrome, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, or isomer thereof.
• the invention provides a method of treating a condition or disease associated with psoriatic arthritis, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I), or a pharmaceutically acceptable salt, solvate, ester, or isomer thereof.
• the invention provides a method of treating a condition or disease associated with multiple sclerosis, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester or isomer thereof, in combination with a compound selected from the group consisting of Avonex®, Betaseron, Copaxone or other compounds indicated for the treatment of multiple sclerosis.
• a compound of the present invention may be coadministered or used in combination with disease-modifying antirheumatic drugs (DMARDS) such as methotrexate, azathioprine, leflunomide, pencillinamine, gold salts, mycophenolate mofetil, cyclophosphamide and other similar drugs.
• DARDS disease-modifying antirheumatic drugs
• NSAIDs non-steroidal anti-inflammatory drugs
• COX-2 selective (COX-2) inhibitors such as Vioxx® and Celebrex®
• immunosuppressives such as steroids, cyclosporin, Tacrolimus, rapamycin and the like
• biological response modifiers BRMs
• other anti-inflammatory agents such as p38 kinase inhibitors, PDE4 inhibitors, other chemically different TACE inhibitors, chemokine receptor antagonists, Thalidomide and other small molecule inhibitors of pro-inflammatory cytokine production.
• a compound of the present invention may be co-administered or used in combination with an H1 antagonist for the treatment of seasonal allergic rhinitis and/or asthma.
• H1 antagonists may be, for example, Claritin®, Clarinex®, Allegra®, or Zyrtec®.
• the invention provides a method of treating a condition or disease mediated by TACE, MMPs, TNF- ⁇ , aggrecanase, or any combination thereof in a subject comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt, solvate or isomer thereof in combination with a therapeutically effective amount of at least one medicament selected from the group consisting of disease modifying anti-rheumatic drugs (DMARDS), NSAIDs, COX-2 inhibitors, COX-1 inhibitors, immunosuppressives, biological response modifiers (BRMs), antiinflammatory agents and H1 antagonists.
• DARDS disease modifying anti-rheumatic drugs
• NSAIDs NSAIDs
• COX-2 inhibitors COX-1 inhibitors
• immunosuppressives biological response modifiers
• BRMs biological response modifiers
• the invention provides a method of treating a condition or disease selected from the group consisting of rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, solid tumor growth and tumor invasion by secondary metastases, neovascular glaucoma, inflammatory bowel disease, multiple sclerosis and psoriasis in a subject, comprising: administering to the subject in need of such treatment a therapeutically effective amount of at least one compound of Formula (I) or a pharmaceutically acceptable salt, solvate, ester, or isomer thereof in combination with a therapeutically effective amount of at least one medicament selected from the group consisting of DMARDS, NSAIDs, COX-2 inhibitors, COX-1 inhibitors, immunosuppressives, BRMs, anti-inflammatory agents and H1 antagonists.
• a condition or disease selected from the group consisting of rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, solid tumor growth
• the invention provides a method of treating a condition or disease selected from the group consisting of septic shock, haemodynamic shock, sepsis syndrome, post ischaemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancers such as cutaneous T-cell lymphoma, diseases involving angiogenesis, autoimmune diseases, skin inflammatory diseases, inflammatory bowel diseases such as Crohn's disease and colitis, osteo and rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, adult Still's disease, ureitis, Wegener's granulomatosis, Behcehe disease, Sjogren's syndrome, sarcoidosis, polymyositis, dermatomyositis, multiple sclerosis, sciatica, complex regional pain syndrome, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV
• the invention provides a method for treating RA comprising administering a compound of the formula I in combination with compound selected from the class consisting of a COX-2 inhibitor e.g. Celebrex® or Vioxx®; a COX-1 inhibitor e.g. Feldene®; an immunosuppressive e.g. methotrexate or cyclosporin; a steroid e.g. ⁇ - methasone; and anti-TNF- ⁇ compound, e.g. Enbrel® or Remicade®; a PDE IV inhibitor, or other classes of compounds indicated for the treatment of RA.
• a COX-2 inhibitor e.g. Celebrex® or Vioxx®
• COX-1 inhibitor e.g. Feldene®
• an immunosuppressive e.g. methotrexate or cyclosporin
• a steroid e.g. ⁇ - methasone
• anti-TNF- ⁇ compound e.g. Enbrel® or Remicade®
• the invention provides a method for treating multiple sclerosis comprising administering a compound of the formula (I) in combination with a compound selected from the group consisting of Avonex®, Betaseron, Copaxone or other compounds indicated for the treatment of multiple sclerosis.
• TACE activity is determined by a kinetic assay measuring the rate of increase in fluorescent intensity generated by TACE catalyzed cleavage of an internally quenched peptide substrate (SPDL-3).
• SPDL-3 internally quenched peptide substrate
• the purified catalytic domain of recombinant human TACE (rhTACEc, Residue 215 to 477 with two mutation (S266A and N452Q) and a 6xHis tail) is used in the assay. It is purified from the baculovirus/Hi5 cells expression system using affinity chromatography.
• the substrate SPDL-3 is an internally quenched peptide (MCA-Pro-Leu-Ala-Gln-Ala-Val-Arg-Ser-Ser-Ser-Dpa-Arg-NH2), with its sequence derived from the pro-TNF ⁇ cleavage site.
• MCA is (7- Methoxycoumarin-4-yl)acetyl.
• Dpa is N-3-(2,4-Dinitrophenyl)-L-2,3- diaminopropionyl.
• a 50 ⁇ l assay mixture contains 20 mM HEPES, pH 7.3, 5 mM CaCI 2 , 100 ⁇ M ZnCI 2 , 2 % DMSO, 0.04% Methylcellulose, 30 ⁇ M SPDL-3, 70 pM rhTACEc and a test compound.
• RhTACEc is pre-incubated with the testing compound for 90 min. at 25 0 C. Reaction is started by addition of the substrate. The fluorescent intensity (excitation at 320 nm, emission at 405 nm) was measured every 45 seconds for 30 min. using a fluorospectro meter (GEMINI XS, Molecular Devices). Rate of enzymatic reaction is shown as Units per second.
• compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
• Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
• Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets.
• excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
• the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
• a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in the U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlled release.
• composition is also intended to encompass both the bulk composition and individual dosage units comprised of more than one (e.g., two) pharmaceutically active agents such as, for example, a compound of the present invention and an additional agent selected from the lists of the additional agents described herein, along with any pharmaceutically inactive excipients.
• the bulk composition and each individual dosage unit can contain fixed amounts of the afore-said "more than one pharmaceutically active agents".
• the bulk composition is material that has not yet been formed into individual dosage units.
• An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like.
• the herein-described method of treating a patient by administering a pharmaceutical composition of the present invention is also intended to encompass the administration of the afore-said bulk composition and individual dosage units.
• Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredients is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or a soft gelatin capsules where in the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
• an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
• an oil medium for example peanut oil, liquid paraffin or olive oil.
• Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
• excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylene
• the aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl, p- hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
• preservatives for example, ethyl or n-propyl, p- hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
• Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
• the oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
• Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
• a dispersing or wetting agent e.g., sodium EDTA
• suspending agent e.g., sodium EDTA
• preservatives e.g., sodium EDTA, sodium sulfate, sodium bicarbonate
• the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion.
• the oily phase may be a vegetable oil, e.g., olive oil or arachis oil, or a mineral oil, e.g., liquid paraffin or mixtures of these.
• Suitable emulsifying agents may be naturally-occurring phosphatides, e.g., soy beans, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, e.g., polyoxyethylene sorbitan monooleate.
• the emulsions may also contain sweetening and flavoring agents.
• Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
• sweetening agents for example, glycerol, propylene glycol, sorbitol or sucrose.
• Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
• the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
• This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, e.g., as a solution in 1 ,3-butane drol.
• the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
• sterile fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil may be employed including synthetic mono- or diglycerides.
• fatty acids such as oleic acid find use in the preparation of injectables.
• compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
• suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
• Such materials are cocoa butter and polyethylene glycols.
• creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the invention are employed.
• topical application shall include mouthwashes and gargles.
• the compounds for the present invention can be administered in the intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
• the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
• Compounds of the present invention may also be delivered as a suppository employing bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
• the dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound thereof employed.
• a physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter, arrest or reverse the progress of the condition.
• Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.
• doses of the compound of Formula I useful in the method of the present invention range from 0.01 to 1000 mg per day. More preferably, dosages range from 0.1 to 1000 mg/day. Most preferably, dosages range from 0.1 to 500 mg/day.
• the compositions are preferably provided in the form of tablets containing 0.01 to 1000 milligrams of the active ingredient, particularly 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
• An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0002 mg/kg to about 50 mg/kg of body weight per day. The range is more particularly from about 0.001 mg/kg to 1 mg/kg of body weight per day.
• the active agent of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in dividend doses of two, three or four time daily.
• the amount of active ingredient that may be combined with the carrier materials to produce single dosage form will vary depending upon the host treated and the particular mode of administration.
• Compound 307 was prepared from compound 306 using the procedure found in Tetrahedron 1975, 31, 863-866.
• the two isomers were separated using a chiral OD column. One gram of material was injected into the column and the two peaks were separated by using a solvent mixture of 85% hexanes/ethanol. The second isomer was the desired compound 309B (400 mg, 80%).
• Compound 555B was prepared according to a modification of a procedure described in WO-9846609.
• a mixture of 2-hydroxy-4-methylpyridine 555A (1.50 g, 13.7 mmol), iodine (3.68 g, 13.7 mmol) and sodium carbonate (3.06 g, 28.9 mmol) in water (70 mL) was heated at 70 0 C overnight.
• Step i mCPBA (3.49 g, 77%, 15.6 mmol) was added to an ice-cold solution of Compound 1039A (1 g, 3.9 mmol) in CH 2 CI 2 (19 ml_). The reaction mixture was allowed to warm to rt, and was stirred overnight. The mixture was diluted with CH 2 CI 2 and was washed sequentially with saturated aq sodium bicarbonate and brine. The organic solution was dried over MgSO-J, filtered and concentrated. The resulting crude product was purified by sgc (0-50% EtOAc-hexanes gradient) to afford Compound 1039B (787 mg, 70%).
• Compounds 1039B and 400 were converted to Compound 1039 by applying the procedure described for Examples 300A and 300B.
• Step i A solution of Compound 1055A (300 mg, 1.28 mmol) in DMF (4.3 mL) was treated with solid cesium carbonate (835 mg, 2.56 mmol) followed by iodomethane (0.09 mL, 218 mg, 1.54 mmol). The reaction mixture was stirred overnight at rt. The reaction mixture was diluted with EtOAc, then washed sequentially with water (3x) and brine. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by sgc (0-50% EtOAc-hexanes gradient) to afford Compound 1055B (150 mg).
• Compounds 1055B and 400 were converted to Compound 1055 by applying the procedure described for Examples 300A and 300B.
• Compounds 1061 B and 400 were converted to Compound 1061 by applying the procedure described for Examples 300A and 300B.
• Compounds 1071 B and 400 were converted to Compound 1071 by applying the procedure described for Examples 300A and 300B.
• Compounds 1077B and 400 were converted to Compound 1077 A by applying the procedure described for Examples 300A and 300B.
• Compounds 1080B and 400 were converted to Compound 1080 by applying the procedure described for Examples 300A and 300B.
• Compounds 1081 B and 400 were converted to Compound 1081 by applying the procedure described for Examples 300A and 300B. Analogous procedures were used for the preparation of Compounds 1082, 1083, 1084, 1085, 1086, 1089, 1090, and 1091.
• Step 1 To a solution of 973A (320 mg, 1.62 mmol) in CH 2 Ci 2 (10 mL) at rt was added Et 3 N (0.45 mL, 3.2 rrimol), 973B (375 mg, 1.78 mmol) and DMAP (cat.) . After 30 min, the solvent was removed and the crude material was purified by column chromatography (SiO 2 , 40% EtOAc/Hexanes) to afford 973C (520 mg, 43%).
• Step2 Compound 400 (100 mg, 0.29 mmol) was combined with compound 973C (133 mg, 0.34 mmol), Pd(PPh 3 ) 2 CI 2 (2.2 mg, 0.003 mmol), CuI (5.5 mg, 0.03 mmol), diisopropylamine (0.05 mL, 0.36 mmol) in DMF (1 mL) and stirred overnight at 85°C. The reaction mixture was concentrated and the crude material was purified with TLC plates (SiO 2 , 10% 7N NH 3 in methanol/CH 2 CI 2 ) afforded the desired product 973D (20 mg, 15%) and 973E (20 mg, 14%). Step 3.
• Step 4 Compound 973E (20 mg, 0.04 mmol) was dissolved in 7 M ammonia solution (2 mL) and stirred in a sealed pressure tube at 90 0 C overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was purified with prepative TLC (SiO 2 , 10% 7N NH 3 in methanol/CH 2 CI 2 ) afforded the desired product 973 (12 mg, 60%).
• Step 2 Compound 1251 B (1.219g, 5.32 mmol) was dissolved in CCI 4 (30 mL). NBS (947 mg, 5.32 mmol) and benzoyl peroxide (66 mg, 0.27 mmol) was added. The solution was stirred at 85 0 C for 2 hours. After cooling down, the solid was filtered and the organic layer was washed with water (10 mL). The organic layer was dried over Na 2 SO 4 , concentrated by rotary evaporator, dried under vacuum. The residue was then dissolved in NH 3 -MeOH (7N, 10 mL) and transferred into a 75 mL pressure bottle. The solution was stirred at 90 0 C for over night. The product was purified by C18 chromatography (CH 3 CN/water: 5% to 90%, with addition of 0.1% HCO 2 H) to give compound 1251C ( ⁇ OOmg, 71%).
• Stepi Compound 401 (130 mg, 0.43 mmol) was combined with compound 925B (112 mg, 0.52 mmol), Pd(PPh 3 J 2 CI 2 (6 mg, 0.009 mmol), CuI (12 mg, 0.06 mmol), diisopropylamine (0.1 mL, 0.71 mmol) in DMF (1 mL) and stirred at 85°C for 2 h.
• the reaction mixture was purified on a Gilson reverse phase HPLC (0-40% acetonitrile with Formic acid 0.01% in H 2 O with formic acid 0.01%) afforded the desired product 924(107 mg, 57%).
• Step 2 To a suspension of 2000B (300 mg, 1.39 mmol) and triethylamine (0.39 mL, 2.78 mmol) in CH 2 CI 2 (9 mL) was added acetic anhydride (0.15 mL, 1.53 mmol) at 25 0 C. After stirring at the temperature for 1.5 h, the mixture was poured to a cold water and the resulting precipitate was collected by filtration. The white solid was washed with water and dried under reduced pressure to afford 2000C (323 mg, 90% yield).
• Step 2 A solution of 2001 C (3 g, 7.16 mmol) in THF (30 mL) was treated with TBAF (1 M solution in THF, 10 mL, 10 mmol) at 0 0 C. The mixture was stirred for 1.5 h at the temperature and poured to a mixture of ice-water and EtOAc. The organic layers were extracted by EtOAc and the combined organic solution was washed with brine solution, dried (Na 2 SOiO 1 and concentrated in vacuo to provide crude 400. The crude 400 was placed in a pressure vessel and dissolved in ammonia in MeOH (7 N solution, 60 mL). The solution was heated to 80 0 C for 14 h and cooled to 25 0 C followed by concentration.
• the two isomers were separated using a chiral AD column. One gram of material was injected into the column and the two peaks were separated by using a solvent mixture of 90% hexanes/2-propanol. The first isomer was the desired compound 943F (400 mg, 80%).
• Step 8 Compound 943H (46 mg, 0.1 mmol) was dissolved in 7 M ammonia solution (2 mL) and stirred in a sealed pressure tube at 90 0 C overnight. The reaction mixture was cooled to room temperature and concentrated. The crude material was treated with EtOEt and the solid was collected by suction filtration to provide compound 943 (28 mg, 68%).
• Step 2 A solution of 2014B (600 mg, 1.51 mmol) in THF (10 mL) was treated with TBAF (1 M solution in THF, 1.8 mL, 1.8 mmol) at 0 0 C. The mixture was stirred for 3 h at the temperature and poured to a mixture of ice-water and EtOAc. The organic layers were extracted by EtOAc and the combined organic solution was washed with brine solution, dried (Na 2 SO 4 ), and concentrated in vacuo. The residue was purified by Si ⁇ 2 column chromatography (30% EtOAc in hexane) to afford 2014C (329 mg, 73% yield).
• 2014D (49 mg, 0.11 mmol) was placed in a pressure vessel and dissolved in ammonia in MeOH (7 N solution, 7 mL). The solution was heated to 80 0 C for 18 h and cooled to 25 0 C followed by concentration. The residue was purified by preparative TLC (7% MeOH in CH 2 CI 2 ) to afford hydantoin 2014E (not shown, 35 mg, 84% yield). 2014E (34 mg, 0.089 mmol) was dissolved in 10% MeOH in CH 2 CI 2 (3 mL) and was treated with 4 N HCI in dioxane (0.3 mL). The mixture was stirred at 25 0 C for 18 h and concentrated in vacuo to afford 2014F (34 mg, quant). Step 5
• Step 3 A mixture of 2017B (19.6 mg, 0.103 mmol), 2016B (37 mg, 0.12 mmol), and diisopropylethylamine (0.11 mL, 0.6 mmol) in DMF (0.5 mL) was heated to 60 0 C. The mixture was stirred for 48 h at the temperature and concentrated in vacuo. The residue was purified by preparative TLC (5% MeOH in CH 2 CI 2 ) to afford 2017C (11 mg, 32% yield).
• Example 1087 A mixture of 2017B (19.6 mg, 0.103 mmol), 2016B (37 mg, 0.12 mmol), and diisopropylethylamine (0.11 mL, 0.6 mmol) in DMF (0.5 mL) was heated to 60 0 C. The mixture was stirred for 48 h at the temperature and concentrated in vacuo. The residue was purified by preparative TLC (5% MeOH in CH 2 CI 2 ) to afford 2017C (11 mg, 32% yield).
• Step 2 The transformation of Compound 1087B to Compound 1087C was carried out following the procedure of Sail and Grunewald, in Sail, D.J.; Grunewald, G.L. J. Med. Chem. 1987, 30, 2208-2216.
• Compound 1099 was prepared by following the procedure given in Example 1087, but starting with commercially available 4-methoxyphenethylamine (Compound 1099A) instead of 3-methoxyphenethylamine (Compound 1087A).
• Compound 1570A was prepared from Compound 400 and 4-iodobenzoic acid by sequential application of the procedures given in Parts H and I in Example 400.
• Solid carbonyl diimidazole (19 mg, 0.12 mmol) was added in one portion to a stirred solution of Compound 1570A in THF (200 ⁇ L). The solution was stirred at 70 0 C for 1.5 h, and was subsequently allowed to cool to rt.
• Solid cyclopropanesulfonamide (17 mg, 0.14 mmol) and DBU (43 ⁇ L, 43 mg, 0.29 mmol) were added sequentially and the reaction mixture was stirred at rt for 18 h. The solvent was evaporated and the residue was dissolved in DCM (50 mL).

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